West Nile Virus (WNV) is as model flavivirus and an NIAID Category B infectious/emerging agent. In addition, it is an emerging public health threat and one of the leading causes of mosquito-borne encephalitis in the United States. While the majority of people infected with WNV experience an acute febrile disease a small percentage of individuals progress to CNS involvement and encephalitic disease. Multiple viral and host factors have been identified which contribute to disease and protection during WNV infection. However, it is still unclear as to the inflammatory signals and viral modulatory properties that define the progression of WNV disease to encephalitis in some individuals. Inflammasomes are a major component of the innate immune response to infection and play a critical role in driving immune activation through the activation and secretion of a family of cytokines including IL-1?. Our preliminary studies have identified a requirement for IL-1 signaling and components of the inflammasome in protective immunity against WNV infection. In addition, we have revealed a potential role for the pattern recognition family of sensing molecules (RIG-I-like receptors, RLRs) in driving the activation of IL-1 and inflammasomes. Our goals going forward are to address the interactions between WNV and the inflammasome in vivo and ex vivo. Specifically we will (1) examine the host immune signaling pathways involved in triggering IL-1?, (2) examine the viral factors which act as agonist for inflammasome activation and (3) determine the mechanism by which inflammasome and IL-1 signaling contribute to protective immunity and limit of CNS encephalitic disease by WNV. Together, these studies will allow us to better understand the requirements for inflammatory signaling in immunity to flavivirus infection and will further our ability to modify these pathways or viral factors involved in these responses for therapeutic and preventative action against flavivirus disease. PUBLIC HEALTH RELEVANCE: West Nile Virus (WNV) is one of the leading causes of mosquito-borne encephalitis in the United States. In addition, WNV and its related genus members, including Dengue Virus, are emerging public health threats both in the U.S. and globally. Currently, there are no therapeutics or vaccine strategies for treating or preventing disease mediated by WNV making the development of these tools necessary. Understanding the interactions between flaviviruses and immune signaling pathways like the inflammasome will shed new light into host and viral factors required for protective immunity and lead to the development of novel therapeutics and preventative vaccines against WNV and other related flaviviruses.